Compounds of the perhydrochrysene and related series and preparation thereof



United States Patent COMPOUNDS OF THE PERHYDROCHRYSENE AND RELATED SERIES AND PREPARATION THEREOF R aymond 0. Clinton, North Greenbush Township, Rensselaer County, N.Y., assignor to Sterling Drug Inc., New York, N.Y., a corporation of Delaware No Drawing. Application January 5, 1956 Serial No. 557,433

21 Claims. (Cl. 260-488) 1.2 "11 1s gom). CH: 14

wherein X, X' and X' are divalent groups selected from the class consisting of H =0 and -OR wherein R is selected from the group consisting of hydrogen and acyl groups, n is an integer from 1 to 2, and the corresponding compounds where X is 0 having a double bond in the 4-,5-position.

In the above general formula, when R is an acyl group, the nature of the acyl group is not critical as it is used only as a blocking or protecting means for the hydroxy group. The preferred types of acyl groups are carboxylic acyl groups having a molecular weight less than about 250, and of these a preferred class comprises those derived from lower fatty acids, including lower-alkanoic acids, lower-aliphatic dicarboxylic acids, and monocarbocyclic aromatic carboxylic acids, optionally substituted by one or more inert groups such as nitro, alkyl, alkoxy and halogen. Thus R in the above definition can be loweralkanoyl, such as formyl, acetyl, propionyl, butyryl,

valeryl, isovaleryl, caproyl, etc. wherein the alkanoyl group has from 1 to about 6 carbon atoms; carboxy-loweralkanoyl, such as hemi-malonyl and hemi-succinyl; and

p-nitrobenzoyl.

In the above general Formula A, the numbering of the ring system is given for the case where n is 1. In the case vwhere n is 2, ring D is seven-membered and, is numbered,

monocarbocyclic aroyl, such as benzoyl, p-toluyl and-- 2,880,233 Patented. Mar. 31, 1959 ice The ring enlargementprocess can be repeated, starting with a compound of Formula II, and a compound having a seven-membered ring D (n=2 in the general formula A above) is obtained. This process leads directly to one of the following species:

CH; CH;

The RO groups can be sterically oriented in either the aor B-positions, and the compounds can belong either to the normal series (A/B cis) or the allo series (A/B trans).

A preferred starting material comprises 3a-acetoxyetiocholane-11,17=di0ne; which ,when carried through the: above process produces, 3a-acetoxy-D-homoetiocholane- 11,17a-dione.

The latter-is readily saponified to give Drhomoetiocholan-ii a-Ol-l 1,17a-dione.

The mixture of epimeric 17- ketoetiocholane cyanohydrins can readily be separated if desired. The 17;8-hydroxy-17a-cyano isomer is much more easily acetylated thanthe 17u-hydroxy-17fl-cyano isomer. Thus when the. 3a-acetoxy-l7-cyanoetiocholan-17-ol-ll-one epimeric mix ture is acetylated with acetic anhydride and pyridine under mild conditions, 3a,17/3-diacetoxy-17u-cyanoetiocho1am ll-one can be separated by fractional crystallization. 3&

, acetoxy l'ZB-cyanoetiocholan-17u-ol-1l-one can then be isolated from the mother liquors.

D-homoetiocholan-3m-ol-11,17a-dione and its 3-acyl derivatives are readily converted to other species within the scopeof my invention. For example, D-homoetiocholan- 3a-ol-11,17a-dione is oxidized with chromic acid or an N-haloamide, or by the Oppenauer method to D-hom etiocholane-3,1 1,17a-trione (III) The ll-keto group of D-hornoetiocholane-3a,17a-diolll-one or its esters can then be reduced to an ll-hydroxy group under stronger reducing conditions, as with lithium aluminum hydride to produce D-homoeticholane-Zladlfl,

5 17a-trio] or esters thereof (VI). Reduction with an o o alkali metal-lower-alkanol medium produces a compound I with an Ila-hydroxy group, e.g., D-homoetiocholane-Iam, o 11a,l7a-triol. The orientation of the ll-hydroxy group CH1 OH: is assigned on the basis of ease of esterification. The llfl-hydroxy group cannot be acetylated by conventional [0] methods, whereas the Ila-hydroxy group can be acetylated readily. HO O 16 CH! CH:

OR OR TheJl-keto group of D-homoetiocholan-3a-ol-l1,17adione is more hindered and less readily reduced than 0 E0 the 17a-keto group. Consequently this compound or its 20 0 esters can be selectively reduced to D-homoetiocholane- 3,l 7a-diol-1l-one or its esters by the use of mild re- [H] ducmg conditions as with sodium borohydride. Both the 17am and 17afi isomers (IV and V) are obtained, V with the 17a)? form predominating. Conformational analysis predicts the preferential formation of the 17a/8 VI form, and the configuration has been assigned on this basis. I

Alternatively, both keto groups of D-homoetiocholan- 3a-ol-l1,l7a-dione can be reduced to hydroxy groups, as by the action of excess lithium aluminum hydride, to CHI give directly D -homoctiocholane-3a,11,3,17a-triol. a o D-homoetiocholane-3a,17a-diol-ll-one can be converted to D-homoetiocholan-17a-ol-3,1l-dione by oxidation CH1 3 of the Ila-hydroxy group while the 17a-hydroxy group is protected by esterification. This can conveniently be [H] accomplished as follows: 3a-acetoxy-D-homoetiocholan- R0 17a-ol-l1-one with benzoyl chloride gives the 17a- I benzoate (VII). Selective saponification of the latter 0: gives 17a benzoyloxy D-homoetiocholan-Ba-ol-l l-one Cm (VIII), which is then oxidized with chromic oxide or an N-bromoamide, or by the Oppenauer method to 17abenzoyloxy-D-homoetiocholane-Ia',ll-dione (IX). A final saponification then gives D-homoetiocholan-l7a-ol-3,11-

1v dione (X).

Clh CH:

OH ococtm CH: CH;

CeHsCOC] H2O D CH|COO- CH|COO-\/ VII CH: CH: CHI

OCOCQHI OCOCaHa OH CH; CH: CH:

[0] H10 --0 O HO- 0 0- VI I IX x 5 In species containing two or more keto groups, fewer" than all of the keto groups can be reduced to hydroxy groups by protection of one or more of the keto groups by conversion to a ketal. For example, D-homoetiocholanv and sodium sulfate.

ethanol instead of ethylene glycol "is employed and ketalization takes place in the presence of zinc chloride The ketone can be regenerated by treatment of the hemithioketal with Raney nickel.

.3u-o1=11',17a-dione can be converted to the Hal-ethylene .35 glycol. ketal by treatmeutwith et yleneslyc l in h presence of an acidic substance, e.g-., hydrogen chloride ;or p-toluenesulfon'ic acid under anhydrous conditions. :The ll-keto group, eing more hind re s not form a ketal, and therefore 'can be subsequently reduced with 70 "'lith iurn' aluminum hydride to anllB-hydroxy group. The Fla-ketal group can then be cleaved with aqueous acid ind I)- homoetiocholane 3:1,115 diol 17a-one results i (XIII). Alternatively the keto group can be protected thehcmithidketal (XI); In-this case, p-mercapto-q5 Similarly, both the 3- and 17a-keto groups of D-homoetiocholane-3,11,17a-trione can be ketalized and the 11- keto group reduced to a hydroxy group giving, after cleavage of the ketal groups, D-homoetiocholan-ll-ol- 3,17a-dione (XVI).

(BIL-CHI S OH:

I C Hrs C'Hr-O XIV CHz-CH: g CHI :0 o

CHz-S xv XVI In a like manner, 17a-benzoyloxy-Dwhomoetiocholan- 3,11-dione can be converted to its 3-(p-mereaptoethanol) ketal (XVII). The ll-keto group can then be reduced to hydroxy, and cleavage of the ketal group and saponification of the benzoyloxy group produces D-homoetiocholane-II.17a-diol-3-one (XIX) on. em

C 0 CIHI 0 C O CIR:

CH: OH;

HO CHzCHaOH LlAlHl CHa-S O Hr-o IX XVII CH; CH:

O C 0 CIHI OH.

HO HO OH; CH:

CHs-S v 0 Hr-O XVIII XIX The compounds of the D-homoetiocholane series (nor- All of the transformations described hereinbefore can mal series, A/B cis) are readily converted to compounds be carried out on the compounds of general formula A of the D-homoandrostane series (allo series A/B trans). This is accomplished starting with the compounds of the general formula 3 wherein X is =0 and X is preferably where R is hydrogen or acyl. A double bond is introduced in the 4,5-position by halogenation in the 4-position followed by dehydrohalogenation. Subsequent catalytic reduction of the double bond produces a mixture of the starting D-homoetiocholane derivative and the isomeric D homoandrostane (D-homoetioallocholane) derivative. The latter can be isolated and carried through the numerwhere n is 2 in an entirely analogous fashion to give the corresponding compounds having a seven-membcred ring D.

The following examples will further illustrate the invention.

EXAMPLE 1 (a)I7-cyanaetiocholane-3mJ7-diol-11'one (I; R is H, X is O) A solution of 15.7 g. of potassium cyanide in 24 ml. of water was added to a solution of 9.0 g. of ctiocholan- 3a-ol-11,17-dione in 576 ml. of absolute ethanol at 3 C. Acetic acid (16.9 ml.) was then added dropwise, and the solution was allowed to warm to room temperature with stirring and kept at that temperature for about twenty-three hours. The reaction mixture was then poured into 2 liters of water and the organic material was extracted with three 500 cc. portions of ethyl acetate The ethyl acetate extracts were washed twice with 200 cc. of water, once with 500 cc. of saturated sodium chlm ride solution, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was crystallized from ethyl acetate to give a first crop of 3.51 g., M.P. 203.5-204.5 C., and a second crop of 0.825 g., M.P. 181-183 C. of a mixture of epimeric 17-cyanoetiocholane-3 0:,17-diOl-1 l-ones.

(b) 17-amin0ethyletioch0lane-3aJ7-diol-II-one A solution of 3.51 g. of a mixture of epimeric l7- cyanoetiocholane-3a,17-diol-1l-ones, M.P. 203.5-204.5 C., in 200 cc. of acetic acid was hydrogenated using 1.0 g. of Adams platinum oxide catalyst. The pressure of the hydrogen employed was about 40 lbs. per sq. inch and hydrogenation was complete in about two hours. The spent catalyst was removed by filtration and the filtrate concentrated in vacuo. The residue was dissolved in methanol and the solution again concentrated in vacuo, and water was added to the residue. The material which failed to dissolve was removed by filtration and the aque ous solution containing the acetate salt of 17-aminomethyletiocholane-3a,17-diol-1l-one was used directly in the following ring enlargement reaction.

(0) D-homoetiocholan-3a-ol-11,17a-di0ne (II; R is H, X is 0) lterial was extractedwith 25 cc..of chlordform.and 751cc. of ether. The organic extracts were washed twicewith .50 ml. of saturated sodium chloride-solution, dried over sodium sulfate, filtered and concentrated to dryness in :vacuo. 0.533 g. of crystalline material, M.P. 173187 C. Recrystallization from a benzene-petroleum ether (Skellysolve B) mixture gave D-homoetiocholan-iiwolal1,l7adione, M. P. 193198 C.

Analysis.-Calcd. for C H O C, 75.43; H, 9.50. Found: C, 75.40; H,9.20.

EXAMPLE 2 (a)3a-acetoxy-1 7-cyan0etioch0lan-1 7-01-11 -one (I; R is acetyl, X is O) A solution of about 70 g. (0.2 mole) of- 3a-acetoxy- -ctiocholane-1l,17-dione in 1500 ml. of 95% alcohol was cooled to about C., and 390 g. (6.0 moles) of potassium cyanide was added followed by 277ml. (2.88 g., 4190 moles) of glacial acetic acid added dropwise over a period of forty-five minutes. The reaction mixture was then stirred for one hour at about 0 C. and at room temperature for about three hours. After standing for fifteen hours the reaction mixture was poured into 8 liters of water containing 150 ml. of glacial acetic acid. The resulting solid was collected by filtration, washed with water, dissolved in 2 liters of hot ethyl acetate, and ethyl acetate solution was washed with water, dried over anhydrous sodium sulfate, decolorized with activated charcoal and concentrated to give 689 g. (92.5%) of a mixture of epimeric 3a-acetoxy-l7-cyanoetiocholan-17- ol-11'-ones, M.P. 217-220 C. (dec.).

- (b) 3a-acetoxy-1 7-amin0methyZetiochplan-1 7-01-11 -one A mixture of 70 g. of a mixture of epimeric 3a-acetoxyal.7'-cyanoetiocholan-l7-ol-1l-ones, g. of platinum oxide catalyst and 1500 ml. of glacial acetic acid was hydrogenated at elevated pressure. After two and one-half hours the pressure dropped from 100 lbs. per sq. inch to 45 lbs. per sq. inch and the temperature ranged from to 33 C. The spent catalyst was removed by filtration and the filtrate concentrated to about .100-150 ml., diluted to a volume of 1 liter with water and again filtered. This solution, containing 3a-acetoxy-l7-aminomethyletio -c'hlolan-17-ol-11-one, was used directly in the following ring enlargement reaction.

(c) 3a-acetoxy-D-hom0eti0cholane-11,1 7 a-dione (II; R is acetyl, X is 0) The dilute acetic acid solution of the mixture of epimeric 3a acetoxy 17 aminomethyletiocholan-17-01-11- ones, prepared as described above, was added'to 800 g. of ice, and 25 g. of sodium nitrite in 75 cc. of water was added all at once. The reaction mixture was stirred occasionally and allowed to stand for about fifteen hours. The solid which separated was collected by filtration, washed with water, dried, stirred with 400 cc. of boiling methanol, cooled in an ice bath and again collected by filtration. The product was recrystallized twice from methanol giving 41.5 g. of 3a-acetoxyaD-homoetiocholane- 11,17a-dione, M.P. 17117l.5 C. (corn) (1% in acetone).

Analysis.--Calcd. for C H O4: Found: C, 73.38; H, 8.87.

(d) D-homoeticholan-Sa-Ol-I1,1 7a-dione (H; R is H, X is O) The residue was triturated with ether to :give

resulting solid-was collected by filtration, dried and re- .75

,ture with ml. of anhydrous ether.

crystallized from :dilute methyl alcohol and then from benzene togive D-homoetiocholan-Su-ol-l1,17a-dione 'as long thickneedles, M.P. 205.5-207.5 C. (corn) (1% in chloroform), identical with the substance obtained in Example 1, part .(c).

Analysis.Calcd. for C H O C, 75.43; H, 9.50.

Found: C, 75.36; H, 9.25.

EXAMPLE 3 (a) 3st,] 7p-diacetoxy-1 7a-cyan0etiocholan-11-one A mixture of 10.0 g. of 3a-acetoxyetiocholane-l1,17-

dione, M.P. .154 155 C., :60 g. of powdered potassium cyanide and 250 ml. of 95 alcohol was cooled in an ice-salt bath to 0 C. Glacial acetic acid (42.5 ml.) was then added dropwise during a period of thirty minutes with vigorous stirring. The reaction mixture was then stirred for one hour at 0 C. and for two hours at room temperature and then poured into 2 liters of water containing 22 ml. .of acetic acid. The organic material was extracted with two portions of 500 ml. each of ethyl acetate, and the ethyl acetate extracts were washed with 1 liter of 5% sodium chloride solution and dried. The ethyl acetate solution was filtered, and the filtrate was concentrated to dryness in vacuo. The residue was dissolved in 20 ml. of acetic anhydride and 40 ml. of pyridine and allowed to stand for six hours at room temperature and then at 0 for two days. The mixture was then poured into ice water containing a small .amount of sulfuric acid, the organic material was extractedwith ether, and the ether extracts were-washed with 3% sodium chloride solution and dried over anhydrous sodium sulfate. The ether solution was evaporated to dryness in vacuo and the residue was taken up in .25 ml. .of acetone, and this solution was slowly diluted with 55 .ml. of petroleum The mother liquors from the original 4.8 g. of crude 3a,l75-diacetoxy-17a-cyanoetiocholan-1l-one, obtained in part (a) above, were evaporated to dryness giving 7.0 g. of solid material which was triturated at room tempera- The remaining solid material was collected by filtration, washed with 20 ml. of anhydrous ether and dried at 50 C. giving. 0.39 g., M.P. 217-222 C. The latter material was combined with material obtained in other runs at the same stage (total weight 6.59 g.) and dissolved in ml. of ethyl acetate. The ethyl acetate solution was treated with activated charcoal, filtered and the filtrate concentrated to a volume of 35 ml. Upon cooling'to 0 C. a solid separated Amixtu're of 2.7g. of 3a-acetoxy-l'7B-cyarioetiocholan- '17a-ol-11-one, 20 ml. of pyridine and 40 ml. of acetic anhydride was allowed to stand at room temperature for about fifteen hours. The mixture was then poured-into ice water to which 15ml. of concentrated sulfuric acid .had been added. The organic material was extracted with after cooling for a few hours in the icebox, and this was collected by filtration, washed with methanol and recrystallized from a mixture of ethyl acetate and petroleum ether (Skellysolve B), giving 30:,17an-difl68tOXY-l7B-CY- anoetiocholan-l l-one, M.P. 183-188.5 C. (corr.),

(1% in chloroform). A mixed melting point with the epimeric l7l3-acetoxy-l7u-cyano compound (M.P. 183- 184" C.), obtained above in part (a), was 145-155" C.

Analysis.-Calcd. for C H NO C, 69.21; H, 8.01; N, 3.37. Found: C, 69.68; H, 8.20; N, 3.43.

EXAMPLE 4 D-homoetiochlane-3JL17a-tri0ne D-homoetiocholan-3a-ol-11,17a-dione (2.0 g.) was dissolved in 26 ml. of tertiary-butyl alcohol by warming. Water (1.0 ml.) was then added and the mixture was cooled to 10 C. N-bromoacetamide (0.97 g.) was added with stirring and the mixture was kept for five hours at -'10 C. and then slowly diluted with 156 ml. of water. The resulting solid which separated was collected by filtration, washed with water and dried giving 1.854 g., M.P. 151-153" C. This product was recrystallized from petroleum ether (Skellysolve B) containing a small amount of ethyl acetate, and again recrystallized from dilute methanol to give a sample of D-homoetiocholane-3,11,17atrione, M.P. 161163 C. (corn), [oz] +0.8 (1% in chloroform).

' Analysis.-Calcd. for C H O C, 75.91; H, 8.92. Found: C, 76.07; H, 8.86.

EXAMPLE 5 (a) 3a-acetoxy-D-hom0eti0ch0lan-1 7afl-0l-1 I-one (IV; R is acetyl) A solution of 2.62 g. of powdered sodium borohydride "in 25 ml. of water and 50 m1. of dioxane was added dropwise during a period of twenty minutes to a solution of 25.0 g. of 3a-acetoxy-D-homoetiocholane-1l,l7a,- dione (Example 2) in 250 ml. of dioxane. The mixture was stirred for fifteen minutes at room temperature and then heated on a steam bath for thirty minutes at 49- '52 C. The mixture was then poured into 2 liters of water, the organic material was extracted with ether,

and the ether solution was washed with two portions of (b) D-homoetiocholane-jaJ7a/3-di0l-11-0ne (IV; R is H) A sample of about 2.5 g. of 3a-acetoxy-D-homoetio- .cholan-17afl-ol-11-one was added to 25 ml. of methyl alcohol containing 1.0 g. of potassium hydroxide and the -rnixture was refluxed for one hour. .then poured into 250 ml. of cold water and the solid 75 The mixture was which'separated was collected by filtration, washed with water and dried at 70 C. to give a sample of D-homoetiocholane-3a,l7afl-diol-1l-one, M.P. 245-260 C. When recrystallized twice from methanol a sample was obtained melting at 271.5-280.5 C. (corn, immersed at 261 C.), [a] =+58.6 (1% in methanol).

Analysis.Calcd. for C H O C, 74.95; H, 10.07.

Found: C, 74.83; H, 10.09.

(c) 3a-acetoxy-D-homoetiocholan-I7aa-ol-1I-one (V; R is acetyl) The combined mother liquors from the preparation of the 3a-acetoxy-D-homoetiocholan-17afl-ol-1l-one of part (a),'starting from a total of 50 g, of 3a-acetoxy-D- homoetiocholane-l1,17a-dione, were concentrated to dryness. The residue was taken up in 20 ml. of benzene and diluted with 480 ml. of petroleum ether (Skellysolve B). The latter solution was filtered and chromatographed on 200 g. of aluminum oxide (pre-washed with 10 ml. of acetic acid in 250 ml. of ethyl acetate, twice with 250 ml. of ethyl acetate and three times with 250 ml. of petroleum ether). The column was then eluted with 500 ml. portions of petroleum etherbenzene mixtures of gradually increasing proportion of benzene. The eluates containing 6080% of benzene when evaporated to dryness provided crystalline material with M.P. about 122 C. This solid material was then recrystallized first from an ethyl acetate-petroleum ether mixture and then from higher boiling petroleum ether (Skellysolve C) giving 3a-acetoxy-D-homoetiocholan-17aa ol-1l-one, isomeric with the compound of part (a), M.P. 134-135 C., resolidified, then m. l47148 C., [a] =+57.4 1% in chloroform).

Analysis.-Calcd. for C l-1 0 C, 72.87; H, 9.45. Found: C, 72.87; H, 9.70.

When the chromatographic column in part (0) above was eluted with benzene, the eluates when concentrated to dryness provided crystalline material of M.P. 209- 216 C. The latter material when recrystallized twice from benzene gave 3a-acetoxy-D-homoetiocholane l1 3, l7ap-diol, M.P. 217-218.5 C. (corr), [a] =+56.5 (1% in chloroform).

Analysis.Calcd. for C H O C, 72.48; H. 9.96. Found: C, 72.70; H, 9.98.

The structure was proven by oxidation with chromic acid to 3a-acetoxy-D-homoetiocholane-l1,17a-dione (Example 2c) and acetylation to give 3a-17a,6-diacetoxy-D- homoetiocholan-l lfl-ol (Example 7b) (d) D-hom0etioch0lane-3 11,1 7aa-di0l-1 1 -one (V, R is H) EXAMPLE 6 (a) 3a-acetoxy-17afi-benzoyloxy-D-homoetiocholan-1 1- one (VII) Benzoyl chloride (33.4 g.) was added dropwise under anhydrous conditions over a period of about ten minutes to a solution of 17 g. of 3a-acetoxy-D-homoetiocholanl7a 3-ol-ll-one (prepared as described in Example 5, part (a)) in ml. of pyridine at 0 C. The reaction mix ture was maintained at O-' C. for two: hours after the addition of the benzoyl chloride was complete and al lowed to stand at room temperature for about fifteen hours. Water (18 ml.) was then added dropwise, and the mixture was stirred for four hours at room: temperature and then poured into 2 liters of Water. The oil which separated crystallized slowly and this was collectedv by filtration, washed with water, stirred. with aqueous sodium bicarbonate solution for forty-five minutes, again collected by filtration, washed with water and dried. The resulting 21.6 g. of cream-colored solid was recrystallized from petroleum ether (Skellysolve C) to give 18 g. of 3a acetoxy 17afi benzoyloxy D hometiocholanll-one, M.P. 172l74 C. Further recrystallization gave a sample melting at 180-182 C. (corr.), [a] ="+106.0 1% in chloroform.)

Analysis.-Calcd. fOl' C29H33o5I H, 8.21. Found: C, 74.57; H, 8.00.

(b) 1 7a/3-benzoyloxy-D-h0moeti0cholan-3a-0l-1 I-one (VIII) A solution of 0.65 g. of potassium bicarbonate in 30 cc. of water was added to a hot solution of 2.5 g. of 3a. acetoxy 17a/3 benzoyloxy D homoetiocholanll-one in 120 ml. of methanol. The mixture was refluxed for two hours and twenty minutes and then neutralized with 0.55 ml. of concentrated hydrochloric acid diluted with water. Most of the methanol was removed in vacuo and the residual material was diluted with water and the solid present was collected by filtration, washed with water and dried giving 2.0 g. of 17afl-benzoyloxy- D-homoetiocholan-Zla-ol-ll-one, M.P. 19'1-194 C. This substance was further purified by dissolving it in ethyl acetate, filtering off a small amount of insoluble material, concentrating the filtrate to a small volume and diluting with petroleum ether (Skellysolve B). In this way a sample melting at 203-205 C. (corr.) was obtained, [a] =-l-81.8 (1% in chloroform).

Analysis.-Calcd. for C H O C, 76.38; H, 8.55. Found: C, 76.31; H, 8.36.

(.c) 17afl-benzoylaxy D homoetiacholane 3,11 dione A solution of 5.0 g. of chromic oxide in 50 ml. of acetic acid and ml. of water was added to a solution of 19.4 g. of 17ap-benzoyloxy-D-homoetiocholan- 3a-ol-11-one in 450 ml. of acetic acid and the mixture was allowed to stand at room temperature for twenty hours. Methanol (50 ml.) was then added and after one-half hour the mixture was evaporated nearly to dryness in vacuo. The residual material was treated with diluted hydrochloric acid and a 1:2 mixture of chloroform and ether. The organic layer was separated, washed with water and sodium bicarbonate solution and dried over anhydrous sodium sulfate. The organic extracts were concentrated to a volume of about 40 ml., 75 ml. of ethyl acetate was added, the solution again concentrated to about 40 ml., 75 ml. of petroleum ether (Skellysolve C) was added and the solution again concentrated to about 50 ml. at which point a crystalline solid separated. The mixture was cooled to 0 for about fifteen hours and the solid was collected by filtrationv and washed with petroleum ether giving 15.6 g. of 17aB-benzoyloxy-D-homoetiocholane-3,ll-dione, M.P. 196-197 C. A sample recrystallized successively from ethyl acetate, acetone and methanol had the M.P. 198.5-202" C. (corr.), [a] =|95.2 (1% in chloroform).

Analysis.Calcd. for C H O C, 76.74; H, 8.11. Found: C, 76.96; H, 8.20.

(d) D-homoetiocholan-I 7aB-0l-3,11-di0ne A solution of 1.0 g. of potassium carbonate in 10 cc. of hot water was added to a. solution of 0.5 g, of 17a- 114 benzoyloxy-D-homoetiocholanefi,Il-dione in 50 cc. of refluxing methanol. The mixture was refluxed for two hours, the methanol removed under reduced pressure and the residue diluted with water. The resulting solid was collected by filtration, washed with water, dried and recrystallized twice from benzene to give D-homoetiocholan- 1.7afl-ol-3,l1-dione, M.P. 243-245 C., [a] =+58.4 (1% in. chloroform).

Analysisrcalcd. for C H O C, 75.43; H, 9.50. Found: C, 75.42; H, 9.60.

EXAMPLE 7 (a) D-homoetiocholane-3ozJ1,6,1 7afl-tri0l (VI; R,R' are H) A solution of 3.6 g. of the 3a-acetoxy-D-homoetiochoIan-17ap-ol-11-one obtained in Example 5, part (a) in ml. of dry benzene and 150 ml. of dry ether was gradually added to a suspension of 1.52 g. of lithium aluminum hydride in 150 ml. of dry ether. The reac: tion mixture was stirred and refluxed for one and onehalf hours in a nitrogen atomsphere. Water (55 ml.) was cautiously added, the mixture was stirred for ten minutes and the organic solvents were removed in vacuo. The residue was cooled in ice, and dilute sulfuric acid equivalent to. 5' ml. of concentrated acid was added. The organic material was extracted with ethyl acetate, the ethyl acetate was washed with water and with sodium bicarbonatesolution, dried over anhydrous sodium sulfate and concentrated to a volume of about 10 m1. Petroleum ether (.50 ml., Skellysolve B) was added, and the resulting solid which separated wascollected by filtration, washed with petroleum ether and dried at 70 C. to give 4.0 g. of D-homoetiocholane-3or,115,17aB-triol, M.P. 188-195 C. with sintering at 132 C. When recrystallized from ethyl acetate and then from acetone, a sam ple melting at 204.5-208 C. (corr.) was obtained, [a] =+38.6 (1% in chloroform).

Analysis.-Calcd. for C H O C, 74.49; H, 10.63. Found: C, 74.49; H, 10.94.

(b) 3a,]7a13-diacet0xy-D-homoetiocholan-I13-01 (.VI; R,R are COCH A solution of 0.5 g. of D-homoetiocho1ane-3a,1In, 17ap-triol in 10 ml. of pyridine and 10 ml. of 90-95% acetic anhydride was heated on a steam bath for one hour. The mixture was then poured into ice-water, and the resulting solid was collected by filtration, dried and recrystallized first from ethyl acetate and then from methanol, giving 3a,17a,B-diacetoxy-D-homoetiocholan- -01, m. 252-255 C. (corr.), [a] =+42.7 (1% in chloroform).

By substitution in the foregoing preparation of the acetic anhydride by a molar equivalent amount of propionic' anhydride, butyric anhydride, succinic anhydride,. ben zoyl chloride, p-nitrobenzoyl chloride, p-toluyl chloride, m-methoxybenzoyl chloride, or o-chlorobenzoyl chloride, there can be obtained, respectively, 3a,17afl-dipropionoxy- D-homoetiocholan-llfi-ol (VI; R,R' are COCH CH 3a,17a,B-dibutyroxy-D-homoetiocholan-1lfl-ol (VI; R,R' are COCH CH CH 3a,17aB-di(B-carboxypropionoxy) D-homoetiocholan-llp-ol (VI; R,R' are cocn cmcoon or 3a,l7afi-di(o-chlorobenzoyloxy) D homoetiocholan 12:0 (V I; R3 a BHA 'Q): I

EXAMPLE 8 (a) 3a-acetoxy-D-homoetiocholane-I1,17a-dione 17a-ethylenehemithioketal (XI; R is acetyl) 3a-acetoxy-D-homoetiocholane-l1,17a-dione (7.2 g.) was dissolved in 25 ml. of dioxane by heating. The solution was cooled to about 15 C. and 7.8 g. of freshly distilled beta-mercaptoethanol and 10 g. of anhydrous sodium sulfate were added. The mixture was then cooled to C. and g. of freshly fused zinc chloride was added. After standing for five hours with occasional shaking, water was added and the mixture extracted with chloroform. The chloroform extracts were dried over anhydrous sodium sulfate and concentrated to dryness. The residue was treated with petroleum ether (Skellysolve B) and the resulting crystalline solid collected by filtration, giveng 5.0 g., M.P. 195-205 C. This product was dissolved in 50 ml. of hot ethyl acetate, upon cooling a gelatinous white precipitate appeared which was removed by filtration. The filtrate was concentrated to dryness and the residue recrystallized from methanol containing a few drops of pyridine, giving 3.0 g. of 3a-acetoxy-D-homoetiocholane-l1,17a-dione 17a-ethylenehemithioketal. Another recrystallization gave a sample melting at 229236 C. (corn), [a] =+51.5 (1% in chloroform) AnaIysis.-Calcd. for C H O S: C, 68.53; H, 8.63; S, 7.62. Found: C, 68.10; H, 8.34; S, 7.62.

(b) D-homoetiocholane-3aJ IB-diol-I 7a-one 1 7a-ethylenehemithioketal (XII; R is H) A suspension of 1.52 g. of lithium aluminum hydride in 200 ml. of anhydrous ether was stirred for one-half hour in a nitrogen atmosphere, and 4.2 g. of 3a-acetoxy- D-homoetiocholane-l1,17a-dione 17a-ethylenehemithioketal dissolved in 50 ml. of benzene and 50 ml. of ether was added dropwise over a period of fifteen minutes. The mixture was then refluxed with stirring for three hours and allowed to stand overnight. Water was then carefully added with cooling followed by ml. of 6 N sulfuric acid. The mixture was stirred until all precipitates had dissolved, and the ether layer was separated and washed with water and sodium bicarbonate solution. The extracts were dried over anhydrous sodium sulfate and concentrated to dryness giving 4.0 g. of D- homoetiocholane-311,11 3-diol-17a-one 17a-ethylenehemithioketal, M.P. 196-202 C. Recrystallization first from an ethyl acetate-petroleum ether (Skellysolve C) mixture and then from ethyl acetate alone gave a sample melting at 207-208 C. (corn), [a] =+32.38 (1% in chloroform).

Analysis.Calcd. for C H O S: C, 69.42; H, 9.53; S, 8.43. Found: C, 69.80; H, 10.00; S, 8.17.

( c) D-hom0eti0ch0lane-3a,lIB-diol-17a-one (XIII; R is H) A mixture of about 4 g. of D-homoetiocholane-3a,1lfldiol-l7a-one 17a-ethylenehemithioketal, 15 g. of Raney nickel and 300 ml. of acetone was refluxed for thirty hours. The mixture was then filtered and the filtrate evaporated to dryness in vacuo. The residue was crystallized from an ethyl acetate-petroleum ether (Skellysolve C) mixture, and recrystallized from the same solvent, giving D-homoetiocholane-3a,1lfi-diol-l7a-one, M.P. 160162 C., with sintering at 156 C.

(d) 3a-acetoxy-D-homoetiocholan-11fi-0l-17a-0ne (XIII; R is CH CO) A mixture of about 10 g. of D-homoetiocholane-3a,11B-

diol-l7a-one, cc. of pyridine and 10 cc. of acetic anhydride was heated on a steam bath for one hour, then cooled and poured into 1 liter of water. The solid product was collected by filtration, washed with water and dried at 70 C., giving 11.0 g., M.P. 133-l37 C. After several recrystallizations from dilute methanol there was obtained a sample of 3m-acetoxy-D-homoetiocholan-l118- ol-17a-one, having the M.P. 164-165.5 C. (corn), [u] =+14.5 (1% in chloroform).

Analysis.Calcd. for C H O C, 72.89; H, 9.45. Found: C, 73.08; H, 9.65.

Sodium metal (23 g.) was added as rapidly as possible to a hot solution of 2.3 g. of D-homoetiocholane-Ba,17a}?- diol-ll-one, obtained as described above in Example 5, part (d), in 250 ml. of n-propanol. The reaction mixture was refluxed for about forty minutes, then cooled, and 200 ml. of methanol was cautiously added to remove the excess sodium. Water (250 ml.) was then added, and the organic solvents were removed in vacuo. The solid material was collected by filtration (2.2 g., M.P. 233-240 C.), and recrystallized first from a methanol-ethyl acetate mixture and then from dilute ethanol. The product was dried for eight hours at C. in vacuo, giving D-homoetiocholane-3u,11a,l7a;8-triol, M.P. 241.5-243" C. (corn), [a] =0.54 (1% in dioxane).

Analysis.Calcd. for C H O C, 74.49; H, 10.63. Found: C, 74.80; H, 10.32.

EXAMPLE 10 (a) 3a-acet0Xy-D-h Omoetiocholane-I 1,17a-dione 17a-ethylene glycol ketal A mixture of 25.0 g. of 3a-acetoxy-D-homoetiocholane- 11,17a-dione, prepared as described above in Example 2, part (c), 25.0 ml. of freshly distilled ethylene glycol, 1.0 g. of p-toluenesulfonic acid monohydrate and 500 ml. of benzene was refluxed under a water trap for seven and one-half hours, and then kept at room temperature for about fifteen hours. Pyridine (2 ml.) was then added, and the benzene solution was washed twice with water, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was recrystallized first from petroleum ether (Skellysolve C) and then from 400 ml. of methanol containing four drops of pyridine, giving 3aacetoxy D homoetiocholane 11,17a dione 17a ethylene glycol ketal in two crops, 13.6 g., M.P. 208-2l0 C. and 3.8 g., M.P. 197-200 C.

The combined crops of 3a-acetoxy-D-homoetiocholane- 11,17a-dione 17a-ethylene glycol ketal (17.4 g.), obtained in part (a) above, was reduced with 184 g. of sodium in 2000 ml. of n-propanol according to the manipulative procedure described above in Example 9. The crude product was extracted with methylene chloride, and the extracts were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was dissolved in ml. of anhydrous pyridine and 100 ml. of 90-95% acetic anhydride, and the solution was then heated on a steam bath for one hour. The reaction mixture was concentrated in vacuo to a volume of 25 ml., 25 ml. of pyridine was added, and the mixture was then added to ice water. The solid material was collected by filtration, dried and recrystallized twice from absolute ethanol containing a few drops of pyridine, giving 14.0 g. of 3u,lla-diacetoxy-D- homoetiocholan-17a-one 17a-ethylene glycol ketal, M.P. 206-208 C.

(0) 311,1 1a-diacetoxy-D-h0moeti0cIz0lan-17a-0ne (II; R is CHECO, X is OCOCHz) A solution of 14.0 g. of 3a,lla-diacetoxy-D-homoetioet1ocholan-17a-one, 9.0 g. of potassium carbonate, 300

. 17 80% acetic acid was heated on a steam bath for one and one-half hours. The reaction mixture was added, to 1 liter of water, and the solid product was collected 'by filtration, giving 12.6 g., M.P. 157-164 C. The latter was recrystallized from 75 ml. of absolute ethanol and dried at 70 C., giving 6.6 g. of 3u,1lot-diacetoxy-D-homoetiocholan-17a-one, M.P. 171-173 C.

(II;RiS H,Xis OCOGHa) A mixture of about 20 g. of 3a,11a-diacetoxy-D-homoetiocholan-17a-one, 9.0 g. of potassium carbonate, 300 ml. of methanol and 50 ml. of water was refluxed on a steam bath for one hour. The reaction mixture was concentrated in vacuo, water was added, and the solid product was collected by filtration, giving 14.3 g., M.P. 153- 160 C. The latter product was recrystallized twice from ethyl acetate and dried for eight hours at 110 C. in vacuo, giving 11oz acetoxy D homoetiocholan 3a l-17aone, M.P. 167-168.5 C. (corn), [a] =--70.9 (1% in chloroform) Analysis.-Calcd. for C H O Found: C, 72.94; H, 9.31.

EXAMPLE 11 (a) 4-bromo-D-h0m0eti0ch0lane-3,11,17a-tri0ne (XX; X',X" are 0) D-homoetiocholane-El,11,-17a-trione (12.235 g., prepared as described above in Example 4) was dissolved in 150 ml. of acetic acid, and 0.2 ml. of 30% hydrogen bromide in acetic acid was added. A solution of 14.20 g. of pyridinium bromide perbromide and 5.16 g. of sodium acetate tetrahydrate in 100 ml. of acetic acid was then added dropwise with stirring and heating. After the addition was complete, the reaction mixture was added to two liters of water, and the solid material was collected by filtration, and dried at 40 C., giving 13.4 g. of 4-bromo- D-homoetiocholane3,11,17a-trione, M.P. 188-190" C. (dec.). A sample when recrystallized from acetone had the M.P. 204-206 C.

(b) D-homo-4-androstene-3J 1 ,1 7a-trione (XXI; X, X" are 0) A mixture of 3.16 g. of 4-bromo-D-homoetiocholane- 3,11,17a-trione and 1.02 g. of anhydrous lithium chloride in 40 ml. of dimethylformamide was heated with stirring on a steam bath for two hours under a nitrogen atmosphere. The reaction mixture was diluted with an equal volume of water and cooled in a refrigerator. The solid product was collected by filtration, recrystallized from ethyl acetate and dried over phosphorus pentoxide at 50 C. for fifteen hours in vacuo and then at 110 C. for seven hours, giving D-homo-4-androstene- 3,11,17a-trione, M. P. 207209 C. (corn),

(1% in chloroform).

Analysis.-Calcd. for C H O C, 76.40; H, 8.34. Found: C, 76.33; H, 8.32.

By substitution in the preceding example of the D- homoetiocholane-3,11,17a-trione by an equal quantity of D-homoetiocholan-17a13-o1-3,11-dione (Example 6, part (d)) there can be obtained D-homo-4-androsten-17afl-ol- 3,11-dione H (XXI; x is 0, X is f-orr EXAMPLE 12 D-hom0andr0stane-3,'11 ,1 7a-trione (XXII; X, X are 0) A solution of 6.0 g. of D-homo-4-androstene-3,11,17atrione, M. P. 1-95-204 C., in 200 ml. of absolute ethanol was hydrogenated in the presence of 0.5 g. of 22% palladium hydroxide 'on strontium carbonate catalyst at 29-30 C. and an initial hydrogen pressure of 31.9 lbs. per sq. inch. After twenty-five minutes the reduction was complete, the catalyst was removed by filtration and the filtrate concentrated in vacuo; The residue was dissolved in ml. of acetone and 20 ml. of water, 2 g. of N-bromoacetamide was added and the mixture was kept at 0 C. for twelve hours. Zinc dust (5 g.) was then added, and the mixture was stirred for fifteen minutes and filtered. The filtrate was concentrated, the residue was Washed with water and the solid material collected by filtration. The latter was recrystallized successively from acetone, ethyl acetate, and absolute ethanol, and dried over phosphorus pentoxide for twenty-four hours at room temperature and then for seven hours at C. in vacuo (1.5 mm., giving 'D- homoandrostane-3,11,17a trione, M. P. 219.5-226.5 C. (corn), [a] =0 (1% in chloroform). This com pound is isomeric with the compound of Example'4,

EXAMPLE 13 3a-acetoxy-D-bishomoetiocholane-I1 ,1 7b-dione (A;Xisl... OCOGHs, X, X"are O,nis 2) A mixture of 3.60 g. of 3a-acetoxy-D-homoetiocholane- 11,17a-dione, prepared as described above in Example 2, part (c) and 10 cc. of acetone cyanohydrin was heated briefly on a steam bath until solution was complete. The reaction mixture was allowed to stand for fifteen hours at room temperature, 200 cc. of water was then added, and the crystalline material which formed was collected by filtration, giving 3.885 g. of 3a-acetoxy-17- cyano-D-homoetiocholan-17a-ol-1 l-one.

The 3a-acetoxy-17-cyano D-homoetiocholan-17a-ol-11- one was hydrogenated with 1.0 g. of platinum oxide catalyst and 200 cc. of acetic acid according to the manipulative procedure described above in Example 1, part (b). The 3a-acetoxy-l7-amir1omethyl-D-homoetio: cholan-17a-ol-1l-one thus obtained was reacted with 1.38 g. of sodium nitrite and 2 cc. of acetic acid in 200 cc. of water according to the manipulative procedure described above in Example 1, part (c). The product separated as a solid from the reaction mixture, and it was collected by filtration and washed with water, giving 3.485 g., M. P. -144 C. After three recrystallizations from methanol there was obtained a sample of 3a-acetoxy-D-bishomoetiocholane 11,17b-dione, M. P. 174.5-175.5 C. (corn), [a] ='-|-16.9 (1% in chloroform).

Analysis.-Calcd. for C H O C, 73.76; H, 9.15. Found: C, 75.40; H, 9.27.

By substituting 3a-acetoxy-D-bishomoetiocholane-11, 17b-dione for the 3a-acetoxy-D-homoetiocholane-11,17adione in Example 3(d) and carrying the resulting D- bishomoetiocholan-3 oc-Ol-l 1,17b-dione.

(A;Xis l OH, X, X are 0, n is 2) or its 3-acetate through the manipulative procedures of Examples 4, 5, 6, 7 and 8, there can be obtained D- bishomoetioch-olane-3,11,17b-trione (A; X, X', X" are 0, n is 2), D-bishomoetiocholane-3a,17bfl-diol-1l-one H p H (A;Xis I 0H,X'ls o,x"is :-0H,n1s2) D-bishomoetiocholan-l7b 8-ol-3 ,1 I-dione (A; X is 0, X is 0, X" is :0H, nis2) D-bishomoetlocholane- 3 a, l 1p,t7 bB-trio1 I H n H (A;Xls l on, X'ls fon, X' n E-orr, ale 2 and D-bishomoetiocholane-3u,11fl-diol-17b-one H H (A; Xls I .OH, Xls E-orr, Xls 0,11152 The compounds of the invention have been found to possess hormone-inhibitory properties when tested in experimental animals, which indicates their usefulness in combatting pathological conditions brought about by endocrine imbalance in the animal organism. For example, D-homoetiocholan-3a-ol-l1,17a-dione (Example 1) was found to exhibit 35.7% inhibition of estrogen at a dose of 5.0 mg./ kg. of body weight per day over a period of three days when measured in female rats by determining the weight of the uteriof the animals injected with the new compound as compared with the weight of the uteri of animals injected only with the standard dose of estradiol. D-homoetiocholane-3'x,1la, 17aB-triol (Example ;9) atadose level of 14 mg./kg., exhibited appreciable inhibitory, effects againstco'rtisone in adrenalectomized rats as measured by the liver glycogen deposition test. 11lotvacetoxy-D-homoetiocholan- 3u-ol-l7a-one (Example 10) was found to exhibit 39% inhibition of androgensat a dose level of mg./kg./day. 3a-acetoxy-D-bishomoetiocholane-11,17b-dione (Example 13) was found to exhibit 30.7% inhibition of estrogen at a dose level of 5 mg./ kg./day. D-homo-4-androstene- 3,11,17a-trione (Example 11) and D-homoandrostane- 3,11,17a-trione (Example 12) were found to possess a pituitary inhibitory potency about equal to that of estosterone when measured by the testicular weight changes in immature male rats, and they possess androgenic activity, although significantly less than that of testosterone; this is an advantage since it indicates that pituitary inhibition may be effected without simultaneously introducing undesirable masculi nizing side-effects.

The compounds of the invention can be prepared for use by dissolving them in a therapeutically acceptable oil or oil-water emulsion for parenteral administration, in the same way that conventional steroidal hormones are formulated.

The compounds of the invention are also useful as intermediates in the preparation of other useful compounds. 'The compounds having a keto group in the 17aposition can be reacted with alkali metal acetylides to give the 17a-ethynyl-I7a-hydroxy compounds which possess estrogen inhibitory properties. The latter are described in my copending application, Serial No. 475,- 810, filed December 16, 1954, now US. Patent No. 2,822,382. The said 17a-ethynyl-17a-hydroxy compounds are in turn useful as intermediates in the preparation of analogous, compounds having the typical cortical hormone side chain, i. e., '-COCH OH, and having that activity, as disclosed in my copending application, Serial No. 463,055, filed October 18,1954, now US. Patent 2,860,158.

" This application-is a continuation-in-part of my copending application, Serial No. 333,615, filed January 27, 1953, now abandoned.

I claim:

1. A compound selected from the group consisting of (A) compounds havin the formula I arm (C Hz) a CH3 wherein n is an integer from 1 to 2.

3. A compound having the formula 4. A compound having the formula 5. A compound having the formula 6. A compound having the formula v CH2 v CH:

OHIO O O 7. D-homoetiocholan-3a-ol-1 1,17a-dione.

8. 3a-acetoxy-D-homoetiocholane-1 1,17a-dione.

9. D-h0moetiocholane-3,l1,17a-trione.

10. D-homoetiocholane-3a,11,17afi-triol.

11. D-homo-4-androstene-3,l 1,17a-trione.

12. 3a-acetoxy D homoetiocholan-lhp-ol-l l-one.

13. D-homoetiocholanl7afi-olv3,ll-dione. 1. ,14. 3a-acetoxy-D-homoetiocholan-11fl-ol-17a-one.

21 22 15. D-homoetiochoIane-ZiaJ1a,l7aB-trio1. 20. The process for preparing a compound having the 16. 1 1a-acetoxy-D-homoetiocholan-3a-ol-I7a-one. formula 17. 3a-acetoxy-D-bishomoetiocholane-l l,I7b-dione.

CH 18. The process for preparing a compound having the 8 formula 0 OH; )x

Ha)- om 10 wherein R is a lower-alkanoyl radical, which comprises 0 treating a compound having the formula CH: wherein X is a member of the group consisting of 3H2NH OH H O f =0 and L'OR CH where R is a member of the group consisting of hydrogen and carboxylic acyl groups having a molecular weight less than about 250, and n is an integer from 1 to 2, which comprises treating a compound having the formula R0 CH: with nitrous acid.

CIhNH: 21. The process for preparing a compound having the formula H. CH1 CH: 3 E) R0 OH;

with nitrous acid.

19. The process for preparing a compound having the 011,000 formula which comprises treating a compound having the formula CHzNH: o 0H on. CH3

CHaCOO which comprises treating a compound having the formula with nitrous acid. on.

95's? References Cited in the file of this patent 0 UNITED STATES PATENTS CH 2,324,881 Ruzicka et a1. July 20, 1943 2,351,637 Ruzicka et a1. June 20, 1944 2,672,482 Woodward Mar. 16, 1954 2,686,792 Murray Aug. 17, 1954 H0 2,694,080 Colton Nov. 9, 1954 2,702,811 Colton Feb. 22, 1955 with nitrous acid. 2,732,405 Dodson Jan. 24, 1956 UNITED STATES PATENT OFFICE Certificate of Correction Patent No. 2,880,233 March 31, 1959 Raymond 0. Clinton It is hereby certified that error appears in the printed specification of the above numberedpatent requiring correction and that the said Letters Patent should read as corrected below.

Column 1, line 35, for X at position 3 of Formula A read K= column 3, in the formula, between lines 33 and 41, at the extreme left for RO- at position 3 should read RO column 9, line 28, for and read and the; line 45, for chlolanread cholan-; column 14, line 22, for atoms here read atmosphere; line 69, for 3a,17B- read 3a,17a,8--; column 15, inc 19, for giveng read -giving; line 20, for acetate, read --acetate; column 16, line 50, for gZyZoZ read gZy00Z-; line 75, strike out etioch0lan-17a-on3e, 9,0 g. of potassium carbonate, 300 and insert instead cholan-l7a-one 17a-ethylene glycol ketal in 100 ml. of; column 18, line 17, for (1.5 mm., read --(1.5 mm.), line 62, for dione. read -dione-; column 19, line 75, claim 1, for X at position 3 of formula read X= column 20,1ine 73, claim 12, for -17aB- read -17a,B-

Signed and sealed this 4th day of August 1959.

[snALj Atttestz KARL H. AXLINE, ROBERT C. WATSON, Attasting 07720612 Oommissz'omar of Patents, 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF (A) COMPOUNDS HAVING THE FORMULA 